Reabsorption of bile acids from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol levels can be diminished by reducing reabsorption of bile acids.
One method of reducing the amount of bile acids that are reabsorbed and, thus, reducing serum cholesterol is the oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids are excreted.
Compounds which have been suggested for bile acid sequestration include various ion exchange polymers. One such polymer is cholestyramine, a copolymer of divinylbenzene and trimethylammoniummethyl styrene. It has been long recognized that this polymer is unpalatable, gritty, and constipating. More recently, various polymers have been suggested which are characterized by hydrophobic substituents and quaternary ammonium radicals substituted upon an amine polymer backbone (Ahlers, et al. U.S. Pat. Nos. 5,428,112 and 5,430,110 and McTaggart, et al., U.S. Pat. No. 5,462,730, which are incorporated herein by reference). In some cases, these polymers have had disappointing efficacy and require complex processes for their manufacture.
Fibrates are also a known class of compounds which has been used as cholesterol-lowering agents. Fibrates are peroxisome proliferator-activated receptor antagonist that effectively lower plasma triglycerides by increasing VLDL lipolysis and clearance, and by decreasing hepatic VLDL triglyceride output. Fibrate treatment also raises HDL levels by increasing hepatic HDL synthesis. Examples of fibrates include, Clofibrate (ATROMID-S®), Gemfibrozil (LOPID®), Fenofibrate, Benzafibrate and the compounds listed in Table 1.
Another class of compounds which have been used as cholesterol-lowering agents are nicotinic acid, commonly referred to as niacin, and derivatives thereof. Niacin is a potent triglyceride reducing agent with an HDL-elevating effect. Niacin therapy is prescribed to treat patients with moderate to severe hypertriglyceridemia and does not usually produce a significant LDL cholesterol-lowering effect. Niacin acts within the liver to decrease VLDL triglyceride output and in the periphery to increase its clearance. The side effects of niacin are well-known and usually limit usage. For example, high doses cause pruritis and flushing. In addition, an elevation in liver enzymes, abdominal cramps, diarrhea, nausea and vomiting have been observed. Niacin is available, for example, as NICOLAR® tablets. Nicotinic acid derivatives include, Acipimox, Aluminum Nicotinate, Niceritrol, Nicoclonate, Nicomol and Oxiniacic Acid.
Another class of compounds which are useful in cholesterol-lowering therapy are thyroid hormones and analogs such as Etiroxate, Thyropropic Acid and Thyroxine.
In addition, there are many known cholesterol-lowering agents which are not members of a particular class of agents. These other cholesterol-lowering agents include, Acifran, Azacosterol, Benfluorex, β-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomestrone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazabol, Meglutol, Melinamide, Mytatrienediol, Ornithine, γ-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, α-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xenbucin.
The present invention furthers efforts for treating hypercholesterolemia and atherosclerosis, as well reducing serum cholesterol, by providing a combination therapy approach and a novel pharmaceutical composition useful therefor.